Hepatic Lysosomal Acid Lipase Overexpression Alters Metabolism and Promotes Immune Infiltration on a Western Diet

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipid droplets (LD) in hepatocytes. If untreated, NAFLD can progress to non-alcoholic steatohepatitis (NASH), cirrhosis, or hepatocellular carcinoma. The progression of NAFLD to NASH is associated with increases in cholesterol levels and decreased autophagy and lipophagy flux. Previous studies have shown that the expression of lysosomal acid lipase (LAL), which can hydrolyze both triglyceride and cholesteryl esters, inversely correlates with the severity of NAFLD and NASH. Based on this, we predicted that overexpressing LAL in the livers of mice fed a NASH inducing high fat diet containing high fructose, palmitate, and cholesterol (FPC) would prevent the development of NAFLD/NASH. Mice fed the FPC diet exhibited numerous markers of NASH including hepatomegaly, lipid accumulation, and inflammation. While LAL overexpression did not prevent hepatomegaly, alterations in LD size and number were observed. RNAseq on liver tissue revealed significant increases in mitochondrial and ribosomal mRNAs as a result of LAL overexpression on the FPC diet, and no changes in lipid biosynthetic pathways. Additionally, mRNAs related to immune cell infiltration and inflammation were significantly enriched in LAL overexpressing mice. Mass cytometry analysis also revealed increased hepatic immune cells in mice overexpressing LAL. Overall, hepatic overexpression of LAL drove immune cell infiltration and inflammation, and did not prevent the development of NAFLD suggesting that targeting LAL activation is not a viable route to treat NAFLD/NASH.